title: Six cases with severe insulin resistance (SIR) associated with mutations of insulin receptor: Is a Bartter-like syndrome a feature of congenital SIR?
abstract: Biallelic insulin receptor (INSR) gene mutations cause congenital syndromes of severe insulin resistance (SIR) known as Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS). At presentation, DS and RMS are difficult to differentiate since they share many clinical features; however, while patients with DS usually die within 1 year of birth, individuals classified as RMS can reach adult age. INSR mutations can be also found in pubertal females with hyperinsulinism, hyperandrogenism, and acanthosis nigricans (type A SIR). We studied the INSR gene in five subjects with congenital SIR and in a patient with type A SIR. Nine biallelic INSR gene mutations (eight novels, including an in-frame deletion of INSR signal peptide) were identified in patients with congenital SIR; a heterozygous, spontaneous INSR mutation was detected in the patient with type A SIR. Two probands, presenting severe hirsutism at birth, died at the age of 3 months and were classified as DS, while other 2, currently 2 and 3 years old, were diagnosed with RMS (patients 3 and 4). The fifth patient with congenital SIR died when 14 months old. Nephrocalcinosis, hyperaldosteronism, hyperreninemia, and hypokalemia, in the absence of hypertension, were discovered in patients 3 and 5 when 24 and 4 months old, respectively. Patient 3, now 3 years/3 months old, still shows hyperreninemic hyperaldosteronism requiring potassium supplementation. We conclude that renal abnormalities resembling antenatal Bartter's syndrome type II, recently reported also by others, is a common observation in patients with congenital SIR.
authors.affiliation: Laboratory of Mendelian Diabetes, Bambino Gesù Childrens' Hospital, Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Grasso
authors.forename: Carlo
authors.initials: C
authors.lastname: Colombo
authors.forename: Valeria
authors.initials: V
authors.lastname: Favalli
authors.forename: Alfonso
authors.initials: A
authors.lastname: Galderisi
authors.forename: Ivana
authors.initials: I
authors.lastname: Rabbone
authors.forename: Sara
authors.initials: S
authors.lastname: Gombos
authors.forename: Enzo
authors.initials: E
authors.lastname: Bonora
authors.forename: Ornella
authors.initials: O
authors.lastname: Massa
authors.forename: Franco
authors.initials: F
authors.lastname: Meschi
authors.forename: Franco
authors.initials: F
authors.lastname: Cerutti
authors.forename: Dario
authors.initials: D
authors.lastname: Iafusco
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bonfanti
authors.forename: Carla
authors.initials: C
authors.lastname: Monciotti
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Barbetti
mesh_terms: D000052:Acanthosis Nigricans / Q000150:complications / Q000175:diagnosis / Q000235:genetics; D000293:Adolescent; D001477:Bartter Syndrome / Q000175:diagnosis / Q000235:genetics*; D002675:Child, Preschool; D056731:Donohue Syndrome / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D009154:Mutation; D009397:Nephrocalcinosis / Q000150:complications / Q000175:diagnosis / Q000235:genetics; D011972:Receptor, Insulin / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D011972:Receptor, Insulin